U.S. patent application number 16/080248 was filed with the patent office on 2019-02-14 for preparation containing esomeprazole.
The applicant listed for this patent is YOO YOUNG PHARM. CO., LTD.. Invention is credited to Jung Ju KIM, Yun Mo KUK, Hyung Min SON.
Application Number | 20190046459 16/080248 |
Document ID | / |
Family ID | 59744180 |
Filed Date | 2019-02-14 |
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United States Patent
Application |
20190046459 |
Kind Code |
A1 |
KIM; Jung Ju ; et
al. |
February 14, 2019 |
Preparation Containing Esomeprazole
Abstract
The present invention relates to a preparation containing
esomeprazole as an active ingredient. The present invention is
characterized in that a controlled-release system is introduced
such that the efficacy of esomeprazole, which is an active
ingredient, can be continuously exhibited.
Inventors: |
KIM; Jung Ju; (Seoul,
KR) ; KUK; Yun Mo; (Seoul, KR) ; SON; Hyung
Min; (Seoul, KR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
YOO YOUNG PHARM. CO., LTD. |
Seoul |
|
KR |
|
|
Family ID: |
59744180 |
Appl. No.: |
16/080248 |
Filed: |
January 17, 2017 |
PCT Filed: |
January 17, 2017 |
PCT NO: |
PCT/KR2017/000550 |
371 Date: |
August 27, 2018 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 1/04 20180101; A61K
31/4184 20130101; A61K 9/5078 20130101; A61K 9/16 20130101; A61P
43/00 20180101; A61K 31/4439 20130101 |
International
Class: |
A61K 9/50 20060101
A61K009/50; A61K 31/4439 20060101 A61K031/4439 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 29, 2016 |
KR |
10-2016-0024669 |
Claims
1. A preparation comprising a plurality of unit sections including
a first section pellet comprising an inert core, a drug layer
coated on the inert core, and an outermost layer coated with an
enteric layer; and a second section pellet comprising an inert
core, a drug layer coated on the inert core, and an outermost layer
coated with an enteric layer, wherein the drug layer of the first
section pellet contains esomeprazole as an active ingredient, and
the drug layer of the second section pellet contains esomeprazole
as an active ingredient and meglumine as a solubilizer, wherein in
the first section, when testing with 100 rotations per minute
according to the first elution test method, the active ingredient
in the unit section is released in the amount of 5% or less
relative to the total amount until 10 minutes after elution
initiation, and the active ingredient is released in the amount of
80% or more relative to the total amount until 30 minutes, and in
the second section, when testing with 100 rotations per minute
according to the first elution test method, the active ingredient
in the unit section is released in the amount of 5% or less
relative to the total amount until 3 hours after elution
initiation, and the active ingredient is released in the amount of
70% or more relative to the total amount until 5 hours.
2. The preparation according to claim 1, wherein the first section
pellet further comprises a separating layer between the drug layer
and the outermost layer coated with the enteric layer.
3. The preparation according to claim 1, wherein the second section
pellet further comprises a separating layer between the drug layer
and the outermost layer coated with the enteric layer, wherein the
separating layer comprises a sustained release polymer.
4. The preparation according to claim 1, wherein the drug layer of
the second section pellet further comprises a sustained release
polymer.
5. The preparation according to claim 1, wherein the drug layer of
the second section pellet further comprises a surfactant.
6. The preparation according to claim 5, wherein the surfactant is
polysorbate.
Description
FIELD
[0001] The present invention relates to the design of a drug
product containing esomeprazole as an active pharmaceutical
ingredient, and more specifically, to technology for a drug
delivery system of an oral preparation consisting of a plurality of
enteric-coated unit sections.
BACKGROUND
[0002] The development of a drug is carried out according to the
search of an active pharmaceutical ingredient (API) and the
determination of a drug product. Herein, the determination of a
drug product is called formulation. Formulation starts from the
selection of a dosage form.
[0003] According to the classification system in the Korean
Pharmacopoeia, there are 36 kinds of dosage forms; however, the
dosage forms are greatly classified into tablets, capsules,
injections, eye drops, external preparations or other semisolid
forms. The selection of a dosage form is made based upon the
preformulation study result of an API. That is, a dosage form is
chosen from the dosage forms that can optimize the expression of
the pharmacological effects of the API, after conducting searches
on solubility, lipophilicity, pKa, stability in the solution state,
penetrability, stability in the body, Pharmacokinetics (PK), etc.
of the API. Of course, in the selection of the dosage form, a drug
compliance of a patient or an increase of distribution convenience
of a drug is also the matters to be considered.
[0004] After the selection of the dosage form, based upon the
preformulation result of the API, a drug delivery system is
specifically determined. For example, in case where a dosage form
for oral administration, such as a preparation or a capsule, is
selected, if the preformulation result shows that the API
stimulates the stomach, is well absorbed in the small intestine, or
is unstable in the gastric fluid, the drug delivery system is
designed as delayed-release.
[0005] When the selection of the drug delivery system is finished,
the prescription of the drug product is finally made by determining
the ingredients and amounts of additives. As the ingredients of the
additives, materials that are harmless to humans have been known in
HANDBOOK OF PHARMACEUTICAL EXCIPIENTS, etc. and unless there is a
special circumstance, the ingredients are selected from those
materials.
[0006] The present invention relates to the design of a drug
product, and basically contains esomeprazole as an active
pharmaceutical ingredient, and its dosage form is a tablet or
capsule, and it has a delayed-release drug delivery system.
However, there are known inventions containing esomeprazole as an
active pharmaceutical ingredient, wherein an enteric-coated oral
tablet or capsule form is adopted.
[0007] For instance, commercially available "Nexium Tab" is an
enteric-coated tablet containing esomeprazole as an active
pharmaceutical ingredient. In addition, Korean Patent No. 1104349
discloses an enteric-coated tablet and capsule wherein the
insufficiency of the stability and properties of the active
pharmaceutical ingredient of "Nexium Tab" was improved by
solid-dispersingwith magnesium oxide and povidone.
[0008] The enteric-coated tablet disclosed in Korean Patent No.
1104349 will be explained. Said enteric-coated tablet is prepared
through the following process. Povidone is dissolved in ethanol, a
solution in which NaOH is dissolved is added therein and mixed, and
then esomeprazole is added and completely dissolved, and a part of
magnesium oxide is added in this solution and dispersed. This
solution is sprayed to colloidal silicon dioxide and magnesium
oxide in a fluidized bed to prepare a granule. This granule is
mixed with microcrystalline cellulose, crospovidone and magnesium
stearate and tableted to prepare a tablet. The prepared tablet is
coated with HPMC using a tablet coater to make a separating layer,
and is enteric-coated thereon with HPMC P (HP-50) or a methacrylic
ethylacrylate copolymer (1:1).
[0009] Subsequently, the capsule disclosed in Korean Patent No.
1104349 is prepared through the following process. Povidone is
dissolved in ethanol, and magnesium oxide is sprayed thereto, and
then a solution in which esomeprazole is added and completely
dissolved is sprayed to a spherical white sugar in the fluidized
bed to prepare a pellet. This pellet is coated with HPMC, and is
enteric-coated thereon with a methacrylate copolymer dispersion
solution. The capsule is filled with the enteric-coated pellet.
DETAILED DESCRIPTION
[0010] Since esomeprazole has acid lability, this needs to be
enteric-coated. For an enteric-coated preparation, it is an
essential matter to be considered that this preparation is designed
such that the preparation can be rapidly disintegrated in the small
intestine and its active pharmaceutical ingredient can be rapidly
dissolved and absorbed. However, the enteric-coated tablet of Korea
Patent No. 1104349 has a limitation in the disintegration rate
because its surface area is small. In the aspect of the rapid
disintegration, it is desirable to increase the surface area by
making the size small; however, in the case of tablets, when
considering a drug compliance and distribution convenience, there
is a limitation in the reduction of the size. For this reason, it
is advised that an enteric-coated preparation consists of granules
or grains which have a wider surface area than a tablet.
[0011] The capsule of Korean Patent No. 1104349 consists of
enteric-coated pellets. Since the pellet is a kind of granules
which have a wide surface area from the viewpoint of the tablet,
this may be superior to tables in the aspect of the disintegration
rate. However, according to the test results of the present
inventor, the pellets of Korean Patent No. 1104349 have a
limitation in solubilizing the active pharmaceutical ingredient.
Thus, the present inventor undertook the present invention in order
to improve the solubility of the active pharmaceutical ingredient
implemented with the pellets.
[0012] Meanwhile, basically, drugs that exhibit the efficacy fast
after administration and at the same time, last the efficacy for a
long time are better. For this, it is necessary to be designed such
that the concentration is continuously maintained after the
concentration in the plasma of the active pharmaceutical ingredient
released from the drug product rapidly reaches the effective blood
concentration. If the active pharmaceutical ingredient is early
released in the excess amount, there would be no problem in rapidly
reaching the effective blood concentration, but there would be a
difficulty in continuously maintaining the effective blood
concentration. In this aspect, Korean Patent No. 1104349 wherein in
the drug delivery system, only delayed-release is introduced with
consideration for the acid-lability of esomeprazole is insufficient
to last the drug efficacy. Therefore, the present inventor was
concerned in the present invention about the additional
introduction of a release-control system that can maintain the
durability of the drug release.
[0013] Means for Achieving Task
[0014] The present invention has solved the aforementioned task
through the following means.
[0015] (1) A preparation comprising a plurality of unit sections
including a first section pellet comprising an inert core, a drug
layer coated on the inert core, and an outermost layer coated with
an enteric layer; and a second section pellet comprising an inert
core, a drug layer coated on the inert core, and an outermost layer
coated with an enteric layer, characterized in that the drug layer
of the first section pellet contains esomeprazole as an active
ingredient, and the drug layer of the second section pellet
contains esomeprazole as an active ingredient and meglumine as a
solubilizer, wherein in the first section, when testing with 100
rotations per minute according to the first elution test method,
the active ingredient in the unit section is released in the amount
of 5% or less relative to the total amount until 10 minutes after
elution initiation, and the active ingredient is released in the
amount of 80% or more relative to the total amount until 30
minutes, and in the second section, when testing with 100 rotations
per minute according to the first elution test method, the active
ingredient in the unit section is released in the amount of 5% or
less relative to the total amount until 3 hours after elution
initiation, and the active ingredient is released in the amount of
70% or more relative to the total amount until 5 hours.
[0016] (2) The preparation according to (1), characterized in that
the first section pellet further comprises a separating layer
between the drug layer and the outermost layer coated with the
enteric layer.
[0017] (3) The preparation according to (1) or (2), characterized
in that the second section pellet further comprises a separating
layer between the drug layer and the outermost layer coated with
the enteric layer, wherein the separating layer comprises a
sustained release polymer.
[0018] (4) The preparation according to any one of (1) to (3),
characterized in that the drug layer of the second section pellet
further comprises a sustained release polymer.
[0019] (5) The preparation according to any one of (1) to (4),
characterized in that the drug layer of the second section pellet
further comprises a surfactant.
[0020] (6) The preparation according to (5), characterized in that
the surfactant is polysorbate.
Effect of Invention
[0021] The present invention is excellent in the stability of the
active pharmaceutical ingredient even though the present invention
does not form a solid dispersion, unlike Korean Patent No.
1104349.
[0022] In addition, the present invention is excellent in the
durability of the drug efficacy because the drug delivery system is
designed such that the active pharmaceutical ingredient can be
continuously released in the small intestine.
[0023] Further, in case of introducing a delayed-release system
into an enteric-coated pellet, the absorption of the
delayed-released active pharmaceutical ingredient must be possible
within the limited residence time in the small intestine. In this
aspect, the preset invention has no problem because the present
invention is excellent in the solubilization of the active
pharmaceutical ingredient in the sustained enteric-coated
pellet.
[0024] Other additional effects will be explained below.
BRIEF DESCRIPTION OF DRAWINGS
[0025] FIG. 1 shows the elution profiles of the first section
pellet (F1) and the second section pellet (F2) according to the
present invention when conducting the elution test according to the
first elution test method. In FIG. 1, the respective points
indicate values at 10 min, 30 min, 180 min, 300 min and 480 min in
order.
[0026] FIG. 2 shows the comparison of the elution profiles of the
capsule (F3) according to the present invention and the
commercially available control preparation, when conducting the
elution test according to the first elution test method.
[0027] FIG. 3 shows the comparison of the animal test (Beagle) PK
profiles of the capsule (F3) according to the present invention and
the commercially available control preparation.
[0028] FIG. 4 shows the comparison of the animal test (Beagle) PD
profiles (gastric acid secretion inhibition rate) of the capsule
(F3) according to the present invention and the commercially
available control preparation.
[0029] FIG. 5 shows the comparison of the elution profiles
according to the amount of meglumine used.
[0030] FIGS. 6 and 7 show the evaluation of the stability of
esomeprazole in the capsule (F3) according to the present
invention.
[0031] FIG. 8 shows the measurement (SEM) of the surfaces of the
pellet (F2) in which polysorbate 80 was used as the surfactant and
the pellet (F3) in which monoglyceride was used as the surfactant.
The upper figure shows the profile of F2, and the lower figure
shows the profile of F7.
[0032] FIG. 9 shows the similarity between the PK profile and the
elution profile of F3 in the animal test.
BEST MODE FOR EMBODIMENT OF INVENTION
[0033] The present invention contains esomeprazole as an active
pharmaceutical ingredient. Esomeprazole, which is one of omeprazole
racemic mixtures, is a proton pump inhibitor. Since esomeprazole is
effective in inhibiting gastric acid secretion and is useful as an
antiulcer drug, this has been used for the prevention and treatment
of diseases related to gastric acid.
[0034] It has been known that esomeprazole is liable to be
sequentially disintegrated and transformed at an acidic or neutral
pH. Further, the stability of esomeprazole is sensitively
influenced by humidity and an organic solvent. For this reason, for
preparations containing esomeprazole, it was focused on improving
the stability of esomeprazole.
[0035] First, for esomeprazole, it is required to design the drug
delivery system as delayed-release in consideration of
acid-lability. Delayed-release refers to a system for inhibiting
the release of a drug in the stomach and delaying the release until
the drug reaches the intestine. Generally, delayed-release is
introduced in case where a drug is not stable in the gastric mucosa
environment; in case where a drug stimulates the gastric mucosa or
causes side effects such as nausea and vomiting; or in case where a
drug is specifically absorbed well in the small intestine.
[0036] Delayed-release can be implemented by enteric-coating a
tablet or capsule with an enteric polymer, which inhibits or
minimizes the release of a drug in the acidic environment of the
stomach and releases the drug at pH of the intestine. Polymers that
ionize at various pH ranges are commercially available, and
depending on the ionization property of polymers, the delay degree
of the release of the drug after the drug reaches the intestine can
be adjusted.
[0037] When enteric-coating, greatly, the two points should be
considered. First, coating should be evenly made such that the drug
product is not disintegrated at an acidic or neutral pH. Generally,
coating is formed by spraying a coating solution to a tablet or
granule. Herein, if the coating solution is not evenly applied on
the tablet or granule, a part that is insufficiently coated would
protrude, so that the delayed-release of the drug product would be
interrupted. Secondly, the drug product should be rapidly
disintegrated when the drug reaches the absorption target
gastrointestinal tract region. The residence time in each site of
the gastrointestinal tract when the drug product is orally
administered is 2-3 hours in the stomach, 4-6 hours in the small
intestine, and 24-72 hours in the large intestine. As such, the
residence time in the small intestine is longer than that in the
stomach; however, it cannot be assured that this is sufficient time
to remove the coating and disintegrate the drug product. For this
reason, it is necessary to make the surface area of the
enteric-coated tablet or granule large by reducing the size or
making the shape close to the spherical shape.
[0038] Based on the aforementioned concept, the present invention
containing esomeprazole as an active pharmaceutical ingredient was
implemented as an enteric preparation, and particularly, the
prescription was designed such that the basic unit of the
preparation consists of a plurality of pellet sections that have a
relatively small size and have the shape close to the spherical
shape. Sometimes, in the case of implementing a pellet according to
any prescription, there was also a case where the shape is not
close to the spherical shape. It was confirmed, however, that
surprisingly, the prescription according to the present invention
makes it possible to evenly apply the enteric-coating agent and is
designed such that the entire shape is close to the spherical
shape.
[0039] Furthermore, the characteristic of the present invention
lies in that delayed-release is introduced as the drug delivery
system, unlike general enteric preparations. It is sufficient in
the expression of the drug efficacy if an active pharmaceutical
ingredient is absorbed in the body at above effective blood
concentration. For this reason, the excess absorption according to
the large early release of the active pharmaceutical ingredient is
not helpful in the continuous expression of the drug efficacy. If
the drug delivery system of delayed-release is introduced into a
drug product, the continuous expression of the drug efficacy may be
possible. However, there is no commercially available drug that
contains esomeprazole as an active pharmaceutical ingredient
wherein the drug delivery system of delayed-release is applied. The
reason is because the attempt to combine the drug delivery systems
of delayed-release and sustained release was not general and
because there was a technical difficulty in implementing such
system.
[0040] First, in order to delayed-release acid-labile esomeprazole,
it is required to design the prescription which can ensure the
stability of esomeprazole for a long time in the body. As
aforementioned, considering that the residence time in the
gastrointerstinal tract of a drug is 2-3 hours in the stomach and
4-6 hours in the small intestine, in order to delayed-release
esomeprazole, it should be stable for at least 7 hours after oral
administration. However, since the stability of esomeprazole is
considerably sensitive to humidity and a solvent as well as pH,
there was a technical difficulty in securing the stability of
esomeprazole in the drug product remaining in the gastrointerstinal
tract for a long time.
[0041] Next, in order to delayed-release esomeprazole in the small
intestine, it should be solubilized such that the active
pharmaceutical ingredient released from the drug product designed
as delayed-release can also be absorbed in the body within 4-6
hours which are the time the drug medicine residues in the small
intestine. For example, if the active pharmaceutical ingredient is
released when 5 hours passed after the drug product residues in the
small intestine, within the range of total 6 hours for which the
drug product can residue in the small intestine, the absorption in
the small intestine is possible only when the active pharmaceutical
ingredient is rapidly solubilized for the remaining short time.
However, in the past, the prescription study for solubilization of
esomeprazole was insufficient.
[0042] However, in spite of the aforementioned technical
difficulty, the present inventor designed a preparation with the
system comprising a plurality of unit sections including a first
section pellet comprising an inert core, a drug layer coated on the
inert core, and an outermost layer coated with an enteric layer;
and a second section pellet comprising an inert core, a drug layer
coated on the inert core, and an outermost layer coated with an
enteric layer, and at the same time implemented such that the first
section is immediate-released and the second section is
delayed-released, and in particular, the second section pellet
designed to be delayed-released is mixed with meglumine (or
meglumine and surfactant) as a solubilizer of esomeprazole in the
drug layer so as to rapidly solubilize the delayed-released
esomeprazole.
[0043] Hereinafter, the prescription and characteristics will be
explained.
Definition
[0044] In the present specification, "esomeprazole" refers to an
active ingredient exhibiting pharmacological activity, and this
includes all of the forms of the main ingredients such as various
salts, prodrug, etc., that a person skilled in the art can combine.
For example, it should be interpreted that esomeprazole magnesium
trihydrate is also included in "esomeprazole."
[0045] "Pellet" refers to a medicament-containing particle having a
diameter in the range of about 100-1500 microns. A pellet which has
a shape close to the spherical shape is better.
[0046] "Inert core" refers to a medicament-free spherical inert
material, and this is a basic seed for preparing a pellet by
additionally applying an immediate-release drug layer or sustained
release drug layer on its outer portion. For example, sugar sphere
or spherical microcrystalline cellulose, etc. can be used.
[0047] "Surfactant" refers to a material that has hydrophilic
groups and lipophilic groups in the molecule at the same time and
is dissolved or dispersed in a solvent and selectively adhered to
an interface so as to significantly change the property of the
interface. The unlimited examples include sodium lauryl sulfate
(SLS) and poloxamer, etc.
[0048] "Sustained release polymer" refers to a polymer substrate
that makes an active pharmaceutical ingredient to be biologically
available during the duration after the oral administration.
Ingredients that can be used as a sustained release polymer have
been known, and the examples include HPMC, etc.
[0049] "Enteric layer" refers to a layer coated with an
enteric-coating agent that is not dissolved even in any buffered
aqueous solution having about 1.0 to 8.0 of pH. Water-insoluble
polymers that can be used as an enteric-coating agent have been
known, and the examples include ethylcellulose or methacrylic acid
acrylic acid copolymer, etc.
[0050] "First elution test method" refers to the elution test using
the rotating basket method corresponding to Device 1 of the elution
test method defined in the Korean Pharmacopoeia. The elution test
method tests an oral preparation to determine whether the
preparation is suitable for the elution test standard, and this is
one of the test methods for the purpose of preventing significant
biological nonequivalence. The sample of this test is equivalent to
the minimum administration dose, and unless otherwise expressly
provided, this means one tablet for tablets, one capsule for
capsules, and the defined amount for other preparations.
[0051] The elution test methods are divided into 1) the first
method (rotating basket method), 2) the second method (paddle
method), and 3) the third method (Flow-Through Cell method),
depending on the device used. The device of the first method
(rotating basket method) consists of a container of a glass or
transparent chemically inert material with a cap, a motor, a
rotation axis and a cylindrical basket. The container is installed
in the proper size of a constant-temperature water bath or put in a
constant-temperature cover (jacket), etc. and is heated. The
constant-temperature water bath or constant-temperature cover is
adjusted such that when conducting the test, the temperature in the
container is 37.+-.0.5.degree. C. and also the liquid in the
constant-temperature water bath smoothly moves. It should be
careful not to make a shake or vibration caused by the device or
the surrounding environment where the device is installed, other
than the smooth rotation of the stirring unit. It should be made to
observe the sample and the stirring state during the operation. The
container, which is cylindrical while its lower part is
hemispherical, has 1000 mL content, 160.about.210 mm height, and
98.about.106 mm inner diameter, and an edge protrudes on the top of
the container. In order to prevent the evaporation of the test
solution, the container is covered with a cap. The distance of any
part of the rotation axis from the center axis in the vertical
direction of the container should be within 2 mm so as to rotate
smoothly, so that a shake or vibration which influences the result
does not occur. The number of rotations is adjusted such that it
rotates within the range of .+-.4% of the defined number of
rotations. The rotation axis and the basket are made with a
stainless steel or an equivalent inert material. In addition, a
basket coated with metal at a thickness of 2.5 .mu.m can be used.
When starting the test, the sample is put into the dried basket.
During the operation, the distance between the bottom of the inner
side of the container and the end of the lower side of the basket
is fixed to be 25.+-.2 mm.
[0052] Meanwhile, the specific ingredients of various additives
mentioned in the present specification, including "inert core",
"surfactant", "sustained release polymer" and "enteric-coating
agent" can be optionally selected from the pharmaceutically
available materials known in the HANDBOOK OF PHARMACEUTICAL
EXCIPIENTS, etc. unless there is a special limitation.
[0053] First Section Pellet
[0054] The present invention relates to a preparation wherein the
unit sections such as a plurality of pellets are assembled. Among
these pellets, a first section pellet and a second section pellet
are essentially comprised, wherein the first section pellet is
configured to be fast release enteric, and the second section
pellet is configured to be sustained release enteric.
[0055] The first section pellet comprises an inert core, a drug
layer coated on the inert core, and an outermost layer coated with
an enteric layer. A separating layer can be further introduced
between the drug layer and the enteric layer, if necessary.
[0056] The inert core can consist of a generally recognizable size,
component when preparing an enteric pellet. For instance, spherical
sugar sphere having a diameter in the range of 100-1500 micron can
be selected.
[0057] The drug layer coated on the inert core contains
esomeprazole and a binding agent, and can be further mixed with any
additive. As the binding agent, a cellulose derivative can be used,
preferably, methylcellulose, hydroxypropylcellulose or
hydroxypropylmethylcellulose can be used, and more preferably,
hydroxypropylmethylcellulose can be used. As any additive, an
excipient, a disintegrant, a lubricant or a surfactant, etc. can be
mixed.
[0058] According to one embodiment of the present invention, a
surfactant can be mixed with the drug layer. As the surfactant,
polysorbate, sorbitan esters, poly(oxy-1,2-ethanediyl) derivative
can be used, and among these, in the aspect of the expression of
the effect of having a solid surface profile while the shape of the
implemented pellet is closer to the spherical shape, the surfactant
is preferably selected from one or more of polysorbate 20,
polysorbate 40, polysorbate 60 and polysorbate 80, and more
preferably, polysorbate 80 can be adopted.
[0059] Particularly, the present inventor was the first to confirm
the spherical shape through the SEM (Scanning electron microscope)
measurement after the preparation of the product using two kinds of
surfactants whose hydrophile-lipophile balance (HLB) values are
different, and as the result, it was confirmed that polysorbate
having the higher HLB value (HLB.gtoreq.15) served as a preferable
role in the formation of the spherical shape as compared to
monoglyceride (HLB 3.3.about.4.1) having a low HLB value.
[0060] The amounts of the respective ingredients can be properly
selected by a person skilled in the art. For instance, the binding
agent can be comprised in the amount of 5-25 wt. % relative to the
total weight of the drug layer, and the surfactant can be comprised
in the amount of 0.5-5 wt. % relative to the total weight of the
drug layer.
[0061] The drug layer can be applied on the inert core according to
any coating method. For instance, the drug layer can be prepared by
dissolving esomeprazole and the binding agent in purified water and
70% ethanol, dispersing them with an absorbent, and then filtering
it to prepare a coating solution, and then spraying the solution to
the inert core.
[0062] According to one embodiment of the present invention, a
separating layer can be added on the drug layer.
[0063] The separating layer comprises a binding agent and a
lubricant, and can be further mixed with any additive.
[0064] As the binding agent, a cellulose derivative can be used,
preferably, methylcellulose, hydroxypropylcellulose or
hydroxypropylmethylcellulose can be used, and more preferably,
hydroxypropylmethylcellulose can be used.
[0065] As the lubricant, metal salts (talc, magnesium stearate,
calcium stearate, sodium stearylfumarate and zinc stearate) and
non-metal salts (fatty acid esters, fatty acids, alcohols, fumaric
acid, polyethyleneglycol, polytetrafluoroethylene lubricant)
lubricants can be used, preferably, the lubricant is selected from
one or more of metal salt lubricants, and more preferably, talc can
be used.
[0066] The amounts of the respective ingredients can be properly
selected by a person skilled in the art, and it is characterized in
that preferably, the binding agent is comprised in the amount of
2-5 wt. % relative to the total weight of the separating layer
comprising the drug layer, and the lubricant is comprised in the
amount of 2-15 wt. % relative to the total weight of the separating
layer comprising the drug layer.
[0067] The separating layer can be applied on the core of the drug
layer according to any coating method. For instance, the separating
layer can be prepared by stirring the binding agent and talc in
purified water and dispersing it, and then filtering it to prepare
a coating solution, and then spraying the solution to the core of
the drug layer.
[0068] In the first section pellet, an enteric layer is applied on
the outermost layer. The enteric layer can be prepared by adding a
water-insoluble polymer and a plasticizer into a mixed solvent of
water:ethanol=5:95 and stirring and dispersing it to prepare a
coating solution and then spraying the solution to the outermost
layer of the core.
[0069] The enteric layer comprises a water-insoluble polymer, a
lubricant and a plasticizer, and can be further mixed with any
additive. As the water-insoluble polymer, a methacrylic acid
ethylacrylic acid copolymer, a methacrylic acid methylmethaacrylate
copolymer, a hydroxypropylmethylcellulosephthalate,
hydroxypropylmethylcellulose acetate succinate,
polyvinylacetylphthalate or cellulose acetatephthalate can be used,
and preferably, a methacrylic acid ethylacrylic acid copolymer can
be used.
[0070] As the lubricant, metal salts (talc, magnesium stearate,
calcium stearate, sodium stearylfumarate and zinc stearate) and
non-metal salts (fatty acid esters, fatty acids, alcohols, fumaric
acid, polyethyleneglycol, polytetrafluoroethylene lubricant)
lubricants can be used, and the lubricant is preferably selected
from one or more of metal salt lubricants, and more preferably,
talc can be used.
[0071] As the plasticizer, esters such as triethyl citrate,
medium-chain fatty acid triglyceride, diethyl phthalate, dibutyl
phthalate, triacetin, butyl phthalyl butyl glycolate, glyceryl
caprylate ester, etc. and alcohols such as glycerine,
propylenglycol, polyethylene glycol, etc. can be used, and
preferably, triethyl citrate can be used.
[0072] The amounts of the respective ingredients can be properly
selected by a person skilled in the art, and preferably, the
water-insoluble polymer can be comprised in the amount of 10-20 wt.
% relative to the total weight of the first section, the lubricant
can be comprised in the amount of 5-10 wt. % relative to the total
weight of the first section, and the plasticizer can be comprised
in the amount of 2-5 wt. % relative to the total weight of the
first section. The above amount of the water-insoluble polymer is
to obtain the elution result of the first section according to the
present invention, and is to meet the drug release time of Nexium
which is a control preparation.
[0073] The first section pellet has the shape close to the
spherical shape and has a solid surface profile.
[0074] The first section pellet designed such that when testing
with 100 rotations per minute according to the first elution test
method, the active ingredient in the unit section is released in
the amount of 5% or less relative to the total amount until 10
minutes after elution initiation, and the active ingredient is
released in the amount of 80% or more relative to the total amount
until 30 minutes is suitable for achieving the effective blood
concentration. Hereinafter, being suitable means that it is not
that the blood concentration of the drug is too high as the active
pharmaceutical ingredient is released in the excess amount, and on
the contrary to this, it is not that the blood concentration of the
drug cannot reach the effective blood concentration because the
release amount of the active pharmaceutical ingredient is too
small.
[0075] The present invention is implemented by the aforementioned
prescription such that the first section pellet can meet the above
elution pattern.
[0076] Second Section Pellet
[0077] The second section pellet is unit section that
delayed-releases esomeprazole as compared to the first section
pellet.
[0078] The second section pellet comprises an inert core, a drug
layer coated on the inert core, and an outermost layer coated with
an enteric layer. A separating layer can be further introduced
between the drug layer and the enteric layer, if necessary.
[0079] The inert core can be configured along the same lines as
that of the first section pellet.
[0080] The drug layer coated on the inert core contains
esomeprazole, meglumine and a binding agent, and can be further
mixed with any additive. The binding agent and any additive can be
configured along the same lines as those of the first section
pellet.
[0081] Meanwhile, the drug layer of the second section pellet can
be further mixed with any known sustained release polymer, unlike
the drug layer of the first section pellet.
[0082] It is the main point that the drug layer of the second
section is mixed with meglumine. Meglumine is a component generally
known as an alkalizing agent. However, surprisingly, the present
inventor has accidentally found that meglumine could improve the
solubility of esomeprazole, and thus was able to have completed the
present invention. Since the second section pellet is the
delayed-release unit section, the release time of esomeprazole is
later than that of the first section pellet. Thus, when considering
the limited residence time of the drug in the small intestine, the
second section pellet needs to improve the solubility of released
esomeprazole. Examples of solubilizing agents of general drugs
include micronisation of particles, mixing with a poloxamer, and
solid dispersion formation, etc. These are all technologies
applicable in the fast release drug delivery system, and known
technologies for the drug delivery system in which delayed-release
and controlled release are complexed were insufficient.
Particularly, there has been no solubilizing means suitable for
delayed-release and controlled release of esomeprazole. However,
the present inventor was the first to improve the solubility of
esomeprazole designed as delayed-release and controlled release by
mixing with meglumine.
[0083] In addition, the drug layer of the second section can be
preferably mixed with the surfactant that can be mixed in the first
section. In the case of further mixing the surfactant, the
solubility of esomeprazole can be improved according to the
synergistic effect with meglumine, and in addition, if polysorbate
80 is selected from the surfactants, it is possible to prepare a
pellet which has the shape close to the spherical shape and has a
solid surface profile as explained above in the first section.
[0084] The amounts of the respective ingredients can be properly
selected by a person skilled in the art, and preferably, the
binding agent can be comprised in the amount of 5-25 wt. % relative
to the total weight of the drug layer, the surfactant can be
comprised in the amount of 0.5-5 wt. % relative to the total weight
of the drug layer, and meglumine can be comprised in the amount of
25-55 wt. % relative to the total weight of the drug layer in order
to obtain the target elution result of the second section.
[0085] The drug layer can be prepared along the same lines as in
the first section pellet.
[0086] According to one embodiment of the present invention, a
separating layer can be added on the drug layer. The prescription
and preparation method of the separating layer can be made along
the same lines as in the first section pellet. However, the amounts
of the respective ingredients can be properly selected by a person
skilled in the art, and preferably, the binding agent can be
comprised in the amount of 2-5 wt. % relative to the total weight
of the separating layer comprising the drug layer, and the
lubricant can be comprised in the amount of 2-15 wt. % relative to
the total weight of the separating layer comprising the drug
layer.
[0087] In the second section pellet, an enteric layer is applied on
the outermost layer. The enteric layer comprises a water-insoluble
polymer, a lubricant and a plasticizer, and can be further mixed
with any additive. As the water-insoluble polymer, a methacrylic
acid ethylacrylic acid copolymer, a methacrylic acid
methylmethaacrylate copolymer, a hydroxypropylmethyl
cellulosephthalate, hydroxypropylmethylcellulose acetate succinate,
polyvinylacetylphthalate and cellulose acetatephthalate can be
used, and preferably, a methacrylic acid methylmethaacrylate
copolymer can be used.
[0088] Herein, the reason why the water-insoluble polymer of the
first section and the water-insoluble polymer of the second section
are different is because of pH independency that each coating has,
and in L30D55 of the first section, a coating is dissolved at above
pH 5.5, and in water-insoluble polymer L100 of the second section
has pH 6.0 and S100 has pH 7.0, and in order to release the drug at
the desired time at pH 6.5 required in the present invention, L100
and S100 can be mixed for use.
[0089] As the lubricant, metal salts (talc, magnesium stearate,
calcium stearate, sodium stearylfumarate and zinc stearate) and
non-metal salts (fatty acid esters, fatty acids, alcohols, fumaric
acid, polyethyleneglycol, polytetrafluoroethylene lubricant)
lubricants can be used, preferably, the lubricant is selected from
one or more of metal salt lubricants, and more preferably, talc can
be used.
[0090] As the plasticizer, esters such as triethyl citrate,
medium-chain fatty acid triglyceride, diethyl phthalate, dibutyl
phthalate, triacetin, butylphthalylbutylglycolate,
glycerylcaprylate ester, etc. and alcohols such as glycerine,
propylenglycol, polyethylene glycol, etc. can be used, and
preferably, triethyl citrate can be used.
[0091] The amounts of the respective ingredients can be properly
selected by a person skilled in the art, and it is characterized in
that preferably, the water-insoluble polymer can be comprised in
the amount of 5-30 wt. % relative to the total weight of the second
section, the lubricant can be comprised in the amount of 5-10 wt. %
relative to the total weight of the second section, and the
plasticizer can be comprised in the amount of 2-5 wt. % relative to
the total weight of the second section.
[0092] The above amount of the water-insoluble polymer is to
release the drug at a specific time in order to obtain the elution
result of the second section targeted in the present invention.
[0093] The enteric layer can be prepared by putting the
water-insoluble polymer and the plasticizer into a mixed solvent of
water:ethanol=5:95 and stirring and dispersing it to prepare a
coating solution and then spraying the solution to the outermost
layer of the core. The prescription is made such that the enteric
layer of the second section pellet is delayed-released, unlike the
enteric layer of the first section pellet.
[0094] The second section pellet has a shape close to the spherical
shape and has a solid surface profile.
[0095] The second section pellet designed such that when testing
with 100 rotations per minute according to the first elution test
method, the active ingredient in the unit section is released in
the amount of 5% or less relative to the total amount until 3 hours
after elution initiation, and the active ingredient is released in
the amount of 70% or more relative to the total amount until 5
hours is suitable for lasting the efficacy of esomeprazole. Herein,
being suitable means that the blood concentration of the drug can
be maintained at the effective blood concentration
continuously.
[0096] The present invention is implemented by the aforementioned
prescription such that the second section pellet can meet the above
elution pattern.
[0097] Dosage Form
[0098] The preparation of the present invention comprises the first
section pellet and the second section pellet. For instance, the
capsule can be filled with the first section pellet and the second
section pellet to prepare the final drug product. The amounts of
the active ingredients in the first section and the second section
can be designed in the proper amount by mixing them at a proper
ratio by a person skilled in the art. For example, the ratio of the
active ingredients in the first section and the second section can
be designed to be 1:1, and herein, for the specific amounts, 20 mg
each can be mixed on the basis of the active ingredient,
esomeprazole. In the case of preparing as above, the durability of
the efficacy can be superior, as compared to 40 mg drug product
commercially available on the basis of the active ingredient.
MODE FOR CARRYING OUT THE INVENTION
[0099] Hereinafter, the present invention will be explained through
the examples. Meanwhile, it should be noted that the examples do
not limit the scope of the present invention in any way.
EXAMPLES
[0100] 1. Elution Test
[0101] As shown in the following Table 1, the first section pellet
and the second section pellet, which are one embodiment according
to the present invention, were prepared, and then the elution test
was conducted.
[0102] The respective pellets were prepared as below.
[0103] Device used--Glatt, Fluidized bed coater (GPCG-2)
[0104] Preparation of the first or second section drug layer--The
drug layer was prepared by putting 70% ethanol in a stainless steel
vessel, and adding the ingredients of the first or second section
drug layer, except for sugar sphere, and stirring and completely
dissolving it to prepare a coating solution of the drug layer, and
then adding Sugar sphere into GPCG-2 and spraying the prepared
coating solution.
[0105] Preparation of the first or second section separating
layer--The protective layer was prepared by putting purified water
in a stainless steel vessel and adding the ingredients of the first
or second section separating layer and stirring and dispersing it
to prepare a coating solution of the separating layer, and then
putting the prepared drug layer pellet in GPCG-2 and spraying the
prepared coating solution
[0106] Preparation of the first or second section enteric
layer--The enteric layer was prepared by putting 95% ethanol in a
stainless steel vessel and adding the ingredients of the first or
second section enteric layer and stirring and dispersing it to
prepare a coating solution of the enteric layer, and then putting
the separating layer pellet comprising the prepared drug layer in
GPCG-2 and spraying the prepared coating solution.
[0107] The elution test was conducted at pH 6.5, 900 mL, and 100
rpm of the first elution test method among the general test methods
of the Korean Pharmacopoeia.
[0108] The specific test conditions were as below.
[0109] Devise used--Vankel, Dissolution system
[0110] Elution Test Device Operation Conditions
[0111] Elution solution: pH 6.5 buffer solution.sub.-- 1 L solution
in which Potassium phosphate monobasic 6.805 g and sodium hydroxide
1.164 g were put in the container and purified water was added.
[0112] Temperature: 37.+-.0.5.degree. C.
[0113] Amount of elution solution: 900 mL
[0114] Rotation speed: 100 rpm
[0115] The conditions for this evaluation were set similar to
in-vivo behavior of the drug, and it has been generally known that
in-vivo behavior can be identified under the test conditions
(in-vitro).
TABLE-US-00001 TABLE 1 F1 F2 Ingredient first section second
section Drug layer Sugar sphere 21.7 mg 21.7 mg Esomeprazole Mg +
2H.sub.2O 21.7 mg 21.7 mg Hypromellose 2910 13.0 mg 13.0 mg
Polysorbate 80 1.8 mg 1.8 mg Meglumine 65.1 mg Separating
Hypromellose 2910 18.5 mg 18.5 mg layer Talc 18.5 mg 18.5 mg
Enteric Methacrylic Acid Copolymer 12.8 mg layer Dispersion
Methacrylic Acid 45.3 mg Copolymer, Type B Methacrylic Acid 15.1 mg
Copolymer, Type A Talc 6.6 mg 17.8 mg Triethyl Citrate 2.6 mg 10.7
mg
[0116] The result was the same as shown in FIG. 1.
[0117] As shown in FIG. 1, the first section pellet was released in
the amount of 5% or less until 10 minutes after initiating the
elution of esomeprazole and then the release reached up to 80% or
more until 30 minutes, and the second section pellet was released
in the amount of 5% or less until 3 hours after initiating the
elution and then the release reached up to 70% or more until 5
hours. This is obvious when referring to the following Table 2.
Table 2 shows the elution rates (%) at 10 min, 30 min, 180 min, 300
min, and 480 min points in FIG. 1.
TABLE-US-00002 TABLE 2 First section Second section Time Standard
Standard (min) Elution rate (%) deviation Elution rate (%)
deviation 0 0.0 0.0 0.0 0.0 10 0.0 0.0 0.0 0.0 30 85.2 4.1 0.0 0.0
180 61.3 0.5 0.0 0.0 300 47.4 0.4 82.2 1.8 480 31.1 0.4 57.8
1.7
[0118] The background of the configuration of the first section and
the second section lies in the residence time of the drug in the
body. In the case of esomeprazole, it has been reported that as a
drug remains in the gastrointestinal tract for a long time, the
degradability of the drug is high. Thus, most of esomeprazole
preparations minimize the degradation of the drug by fast releasing
the drug in the gastrointestinal tract. However, said products have
a drawback that they cannot prolong the duration time of the drug
in the body. In order to improve this drawback, the present
invention was configured such that in the small intestine, the
first section induces the fast release of esomeprazole, and the
second section induces the secondary release of esomeprazole at a
specific time in consideration of the dissipation rate of the drug
of the first section in the body for the prolongation of the
duration time of the drug in the body.
[0119] 2. Comparative Elution Test
[0120] The capsule was prepared by mixing F1 and F2 of Table 1 at a
ratio of 1:1 on the basis of the amount of the active ingredient
and filling a soft capsule (Cap length 9.7-11.1 mm, Body length
16.5-18.5 mm), which is based on gelatin, with the assembly (F3) of
the unit section comprising the composition of the following Table
3.
TABLE-US-00003 TABLE 3 Ingredient F3 Drug layer Sugar sphere 43.4
mg Esomeprazole Mg + 2H.sub.2O 43.4 mg Hypromellose 2910 26.0 mg
Polysorbate 80 3.6 mg Meglumine 65.1 mg Separating Hypromellose
2910 37.0 mg layer Talc 37.0 mg Enteric layer Methacrylic Acid
Copolymer Dispersion 12.8 mg Methacrylic Acid Copolymer, Type B
45.3 mg Methacrylic Acid Copolymer, Type A 15.1 mg Talc 24.4 mg
Triethyl Citrate 13.3 mg
[0121] The elution profiles of the capsule (esomeprazole 20 mg as
the active ingredient of the first section, esomeprazole 20 mg as
the active ingredient of the second section) which is one
embodiment according to the present invention prepared with the
compositions of the above Table 3 and of "Nexium Tab. (esomeprazole
40 mg as the active ingredient)" which is commercially available
drug product of esomeprazole were compared.
[0122] The result was the same as shown in FIG. 2.
[0123] The evaluation of the subject elution is in-vitro elution
file for predicting in-vivo behavior of the drug. That is, the
presented elution conditions are to identify the matching with the
in-vivo blood concentration profile of the drug (the time when the
drug is released and the time when the drug is delayed, etc.) to
identify whether the set elution test method was proper.
Consequentially, the set elution test method confirmed the identity
of the elution profile with the PK profile of the animal test as
shown in FIG. 9 (30 minutes-1 hour for which the drug of the first
section is released in-vivo at the maximum-1 hour the maximum blood
concentration of the drug of the first section in the animal test/5
hours for which the drug of the second section is released in-vivo
at the maximum-5 hours the maximum blood concentration of the drug
of the second section in the animal test/2-4.5 hours in-vivo
delayed time of the drug between the first section and the second
section and the reduction of the blood concentration of the drug of
the first section and the second section in the animal test) so as
to secure the propriety of the set elution test.
[0124] 3. Animal Test
[0125] Fistula was mounted on test animals, Beagle dogs, in which
Hedenhain pouch was formed by the operation, and then test drug
(F3) and control preparation (commercially available Nexium Tab 40
mg) were orally administered, and the gastric fluid and blood were
collected after 0.5, 1, 1.5, 2, 3, 4, 4.5, 5, 5.5, 6, 7, 8, 10, and
14 hours and analyzed.
[0126] The results were the same as shown in FIGS. 3 and 4.
[0127] The elution patterns of both the control preparation and the
test drug showed significant correlation with the PK profile.
However, in the pharmacodynamic aspect, the delayed-released test
drug inhibited the gastric acid for longer time. Based on this
result, it was confirmed that the test drug has the superior effect
than the control preparation in the inhibition of Proton pump.
[0128] 4. Solubilization Effect Test
[0129] In order to identify the effect of meglumine as the
solubilizer of esomeprazole, the control test was conducted by
changing the compositions as shown in the following Table 4 under
the following conditions.
[0130] Device used--Vankel, Dissolution system
[0131] Elution Test Device Operation Conditions
[0132] Elution solution: pH 6.5 buffer solution.sub.-- 1 L solution
in which Potassium phosphate monobasic 6.805 g and sodium hydroxide
1.164 g were put in the container and purified water was added.
[0133] Temperature: 37.+-.0.5.degree. C.
[0134] Amount of elution solution: 900 mL
[0135] Rotation speed: 100 rpm
TABLE-US-00004 TABLE 4 Ingredient F4 F5 F6 F2 Drug Sugar sphere
21.7 mg 21.7 mg 21.7 mg 21.7 mg layer Esomeprazole 21.7 mg 21.7 mg
21.7 mg 21.7 mg Mg + 2H.sub.2O Hypromellose 2910 13.0 mg 13.0 mg
13.0 mg 13.0 mg Polysorbate 80 1.8 mg 1.8 mg 1.8 mg 1.8 mg
Meglumine 21.7 mg 43.4 mg 65.1 mg Separating Hypromellose 2910 18.5
mg 18.5 mg 18.5 mg 18.5 mg layer Talc 18.5 mg 18.5 mg 18.5 mg 18.5
mg Enteric Methacrylic Acid layer Copolymer Dispersion Methacrylic
Acid 31.7 mg 36.3 mg 40.8 mg 45.3 mg Copolymer, Type B Methacrylic
Acid 10.6 mg 12.1 mg 13.6 mg 15.1 mg Copolymer, Type A Talc 17.8 mg
17.8 mg 17.8 mg 17.8 mg Triethyl Citrate 10.7 mg 10.7 mg 10.7 mg
10.7 mg
[0136] The result was the same as shown in FIG. 5.
[0137] Solubilization of the drug was improved when meglumine was
used.
[0138] 5. Stability Test
[0139] The stability of F3 which is one embodiment of the present
invention was evaluated.
[0140] The total flexible materials were evaluated by conducting an
Open severe test for the preparation (HDPE bottle with no cap at
relative humidity 75% and 50.degree. C.). The flexible materials
during each period were indicated with flexible material %. As the
result, it was confirmed that the test drug of the present
invention was stable since there was no significant difference
between the raw material that has stability and the test drug (F3)
as shown in FIGS. 6 and 7.
[0141] 6. Test for Profile of Pellet
[0142] The pellet was prepared with the compositions of the
following Table 5 and then the profile was measured.
[0143] Device used--Glatt, Fluidized bed coater (GPCG-2)
[0144] Preparation of the drug layer--The pellet was prepared by
putting 70% ethanol in a stainless steel vessel, and adding the
ingredients of the F2/F3 drug layer, except for sugar sphere, and
stirring and completely dissolving it to prepare a coating solution
of the drug layer, and then putting Sugar sphere into GPCG-2 and
spraying the prepared coating solution to prepare the drug layer
pellet, and then the profile was measured.
TABLE-US-00005 TABLE 5 Ingredient F2 F7 Drug layer Sugar sphere
21.7 mg 21.7 mg Esomeprazole Mg + 2H.sub.2O 21.7 mg 21.7 mg
Hypromellose 2910 13.0 mg 13.0 mg Polysorbate 80 1.8 mg
Monoglycerid 1.8 mg Meglumine 65.1 mg 21.7 mg
[0145] The result was the same as shown in FIG. 8. This is the
profile of the pellet in which only the drug layer was coated.
[0146] For constant drug release, the pellet needs to have the
shape close to the spherical shape. In this test, the spherical
shape was confirmed through the SEM (Scanning electron microscope)
measurement after the preparation of the product using two kinds of
surfactants whose hydrophile-lipophile balance (HLB) values are
different, and as the result, it was confirmed that polysorbate
having a higher HLB value (HLB.gtoreq.15) served as a preferable
role in the formation of the spherical shape as compared to
monoglyceride (HLB 3.3.about.4.1) having a low HLB value.
* * * * *